Distinct Regulation of Iron Homeostasis in Rat Heart and Liver in Response to Systemic Iron Deficiency

Chronic heart failure (HF) is characterized by severe cardiac mitochondrial dysfunction. Cellular energetic function is importantly regulated by iron since mitochondrial enzymes involved in oxidative phosphorylation, antioxidative defense and oxygen transport require iron-containing cofactors (heme, Fe-S clusters). In HF, systemic iron deficiency (ID) shows high prevalence (30–50%) and is associated with worse exercise capacity and increased mortality. Human and animal studies showed discordant results concerning iron content in failing heart, even reporting mitochondrial iron overload in some instance. This leads to a controversy of using iron chelation or iron supplementation as metabolic therapy for HF. Our aim was to investigate the regulation of key actors of cellular iron metabolism in the left (LV) and the right (RV) ventricles of two rat models of systemic ID. A comparative study was also performed in the liver, the main iron storage organ known to sense systemic ID. We developed two rat models of systemic ID without anaemia and cardiac remodelling, using low iron diet for 60 days, combined either with two distinct blood withdrawals at day 0 and 30 or with iron chelator deferiprone from day 1 to 60. Control rats were fed on a normal iron diet. Rats were sacrificed at day 60, serum and tissue iron contents were determined using a photometric colorimetric method. mRNA and protein levels of transferrin receptor 1 (TfR1), L-ferritin (L-Ft) and ferroportin (Fpn), involved in iron uptake, storage and export respectively were measured in biopsies of RV, LV and liver. Liver hepcidin, regulating systemic iron homeostasis, was analysed at mRNA level as well as cardiac hepcidin required for autonomous cellular iron homeostasis. Our main results showed that LV and RV maintained their iron content in a physiological range while the liver drastically decreased its iron pool in response to ID. In this condition, the RV exhibited a post-transcriptional regulation of both TfR1, L-Ft and Fpn similarly to the one found in the liver. In contrast, the LV showed a post-translational regulation of TfR1, a potential post-transcriptional regulation of L-Ft and no regulation for Fpn in ID. Our study showed that both ventricles initiate an adaptative response to maintain their physiological iron pool under systemic ID. These results should be confirmed in a HF model with systemic ID to better establish the benefits of iron chelation or supplementation in HF patients.